Malformin A1 Enhances 5-Fluorouracil-induced Apoptosis, Cell Cycle Arrest, and Anti-angiogenesis in Colorectal Cancer Cells.

BACKGROUND/AIM: Malformin A1 (MA1), a fungal-derived cyclic pentapeptide, has been reported to exhibit anti-cancer activity. 5-fluorouracil (5-FU) is a widely used chemotherapeutic agent that inhibits DNA and RNA synthesis and suppresses colorectal cancer (CRC) cell growth. This study aimed to investigate whether MA1 enhances the anticancer effects of 5-FU in CRC cells. MATERIALS AND METHODS: The effects of MA1 and 5-FU on CRC cells were evaluated using the WST-1 cell viability assay, DNA fragmentation analysis, flow cytometry, and western blotting. RESULTS: MA1 treatment demonstrated greater cytotoxic activity in CRC cells compared to 5-FU alone. Combined MA1 treatment enhanced 5-FU-induced apoptosis through activation of PARP, caspase-3, and caspase-9, along with decreased expression of anti-apoptotic proteins Mcl-1 and Survivin, compared with the non-combined treated control. In addition, combined MA1 treatment potentiated 5-FU-induced cell cycle arrest at the sub-G1 phase by increasing p57 protein levels and reducing cyclin D1, CDK6, and Cdc25C protein expression relative to the non-combined treated control. Furthermore, combined MA1 treatment augmented 5-FU-induced inhibition of umbilical vein endothelial cell invasion, tube formation, and the expression of vascular endothelial growth factor (VEGF)-A and -D. The phosphorylation levels of p38 and c-Jun NH2-terminal kinase (JNK) were further upregulated by combined MA1 treatment in CRC cells compared to the non-combined treated control. CONCLUSION: MA1 enhances 5-FU-induced apoptosis, cell cycle arrest, and anti-angiogenic effects in CRC cells through activation of the p38 and JNK signaling pathways. These findings suggest that the combination of MA1 and 5-FU may represent a potential strategy to overcome resistance to 5-FU in CRC cells.